Process and new intermediates for the preparation of 11-methylene steroids

ABSTRACT

A process for the preparation of 11-methylene steroids from di-keto steroids involves selective olefination of the ketone at position 11 of the di-keto steroids. The resulting 11-methylene steroid products can be used as intermediates in the preparation of the synthetic steroids, Etonogestrel and Desogestrel, as well as other pharmaceutically active agents.

PRIORITY AND CROSS REFERENCE TO RELATED APPLICATIONS

This application is the U.S. National Phase Application under 35 U.S.C.§ 371 of International Application No. PCT/EP2017/054952, filed Mar. 2,2017, designating the U.S. and published in English as WO 2017/149091 A1on Sep. 8, 2017, which claims the benefit of European Application No. EP16382092.1, filed Mar. 3, 2016. Any and all applications for which aforeign or a domestic priority is claimed is/are identified in theApplication Data Sheet filed herewith and is/are hereby incorporated byreference in their entirety under 37 C.F.R. § 1.57.

FIELD OF THE INVENTION

The invention relates to a process for the selective olefination of11,17-di-keto steroids to the corresponding 11-methylene-17-ketosteroids, which are useful intermediates in the preparation of severalpharmaceutically active agents, such as Etonogestrel and Desogestrel.

BACKGROUND OF THE INVENTION

Desogestrel and Etonogestrel are synthetic steroids with strongprogestational activity. They are used in third-generation contraceptiveformulations.

Desogestrel is currently used as a synthetic progestin in numerous oralcontraceptive formulations, whereas Etonogestrel is being used assynthetic progestin in the vaginal ring delivery system NuvaRing® and inthe implant Implanon®.

Several synthetic methods have been described in the literature for thesynthesis of these progestin compounds.

Desogestrel and Etonogestrel were described for the first time in theGerman patent DE 2361120 (also published as U.S. Pat. No. 3,927,046)which discloses the synthesis of Desogestrel. The synthesis ofDesogestrel disclosed in U.S. Pat. No. 3,927,046, as well as in Heuvel,M. J., et al. Recueil des Travaux Chimiques des Pays-Bas 1988, vol. 107,no. 4, p. 331-334, employs the compound of formula (IV) as a keyintermediate. This compound is obtained by olefination of the ketone inposition 11 of compound (II), where the ketone groups at positions 3 and17 are protected as ketals, followed by cleavage of the protectinggroups in compound (III).

WO2004/014934 discloses the synthesis of desogestrel from11α-hydroxy-18-methyl-estra-4-en-3,17-dione, which is obtained bymicrobiological hydroxylation in position 11α. Before creating theexo-methylene functionality in position 11, the ketone group at position17 is protected.

Desogestrel and etonogestrel can also be synthesised according to themethod described in CN1865276 A. 11-oxo functionality is obtained byepoxide rearrangement and Birch reduction to afford the compound offormula (I). Olefination at position 11 of intermediate (II) affords thecompound of formula (III), which is used as key intermediate for thepreparation of both desogestrel and etonogestrel.

In order to generate the methylene group at position 11, addition ofmethyl lithium to the 11-keto group was performed over an intermediatecompound substituted at position 17 with a hydroxyl protected group inthe synthesis of etonogestrel disclosed by Gao et al in Steroids 1997,62(5), 398-402.

In Organic Preparation and Procedure Int., 1997, 29(5), 572-576, Gao etal described the synthesis of desogestrel from13β-ethyl-11-hydroxy-gon-4-ene-3,17-dione. Again, olefination of theketone at position 11 is performed after protection of the ketone groupsat positions 3 and 17 as diethylene ketal.

In CN102964418, selective protection of the 3-ketone of13-ethyl-3,11,17-trione (I) as dithioketal followed by protection of the17-carbonyl group in (III) as ketal afforded intermediates (V) and(XIII). Olefination at position 11 of said protected intermediates,deprotection of the dioxolane, ethynylation at position 17 and thioketaldeprotection afforded etonogestrel.

A similar strategy, selective protection of the ketone at position 3 asdithioketal, followed by protection of the 17-keto group with ethyleneglycol, was also used in WO 2013/135744. The 11-methylene derivative(VII) was obtained through Wittig reaction or Peterson olefination.Subsequent alkynylation and deprotection gave rise to etonogestrel.

WO2013/071210 describes the synthesis of compound 9, a key intermediateto desogestrel and etonogestrel. Oxidation of alcohol 5 under Swernconditions yielded ketone 6, which was treated under Petersonolefination conditions. Birch reduction of triene 7 gave rise to diene8, which was hydrolyzed to furnish 11-methylene diketone derivative 9.Again, protection of the 17 ketone was performed prior to olefination atposition 11.

This same key intermediate to desogestrel and etonogestrel was alsoprepared in WO2014/037873. In this case, instead of protecting the17-keto group before carrying out the olefination of the ketone atposition 11, it was reduced to the corresponding hydroxyl compound (V)and then reoxidized to the ketone after the 11-methylene group wasintroduced.

A totally different synthesis of desogestrel was disclosed by Corey etal. in J. Am. Chem. Soc. 1999, vol. 121(4), 710-714, where the steroidbackbone was constructed. This strategy does not seem industriallyapplicable; at least 13 synthetic steps are required to obtain17α-hydroxy-11-methylene-18-methylestr-4-en-3-one.

In summary, the methods disclosed in the prior art for the preparationof etonogestrel and desogestrel are too long and/or not industriallyapplicable. In general, most of the syntheses disclosed compriseolefination of the keto group at position 11. However, in all thesemethods additional steps of protection/deprotection orreduction/oxidation of the 17-keto group are required, which increasesthe number of steps of the synthesis.

It is therefore necessary to develop a new process for obtaining keyintermediates in the synthesis of steroids such as desogestrel oretonogestrel which overcome all or part of the problems associated withthe known processes belonging to the state of the art.

SUMMARY OF THE INVENTION

The invention faces the problem of providing an improved process for thepreparation of 11-methylene-17-keto compounds and derivatives thereof.In particular, the inventors have surprisingly found that 11,17-di-ketosteroids can be selectively olefinated through reaction with a compoundof formula (III) as defined herein. This olefination reaction iscommercially important since the resulting 11-methylene-17-keto steroidsare intermediates in the preparation of therapeutically valuablecompounds, such as e.g. Etonogestrel and Desogestrel.

In addition, the process developed by the inventors allows preparing11-methylene steroids in an efficient manner, using easily availablestarting materials and applying reaction conditions suitable for largescale production.

Thus, in a first aspect, the invention is directed to a process for thepreparation of a compound of formula (I), or a solvate thereof

wherein

-   -   X represents H or it forms together with the carbon atom to        which it is bonded a ketone protecting group;    -   Y together with the carbon atom to which it is bonded represents        C═CH₂ or C(OH)CH₂Z, wherein Z is selected from H and SiR′₃        wherein each R′ is independently selected from C₁-C₆ alkyl and        C₆-C₁₀ aryl;    -   R⁶ is selected from H, C₁-C₆ alkyl and halogen;    -   R¹⁰ is selected from H, C₁-C₆ alkyl and halogen, or is absent        when there is a double bond between C₁ and C₁₀;    -   R¹³ is selected from H and C₁-C₆ alkyl;    -   R¹⁶ is selected from H, C₁-C₆ alkyl and halogen; and    -   is a single or double bond;        which comprises reacting a compound of formula (II) or a solvate        thereof

wherein X, R⁶, R¹⁰, R¹³, R¹⁶, and

can take the meanings defined above;with a compound of formula (III)

wherein Z can take the meanings defined above and M is selected from Li,MgBr, MgCl and Mgl.

In another aspect, the invention is directed to an intermediate compoundof formula (Ic), or a solvate thereof

wherein

-   -   X represents H or it forms together with the carbon atom to        which it is bonded a ketone protecting group;    -   Z is selected from H and SiR′₃ wherein each R′ is independently        selected from C₁-C₆ alkyl and C₆-C₁₀ aryl;    -   R⁶ is selected from H, C₁-C₆ alkyl and halogen;    -   R¹⁰ is selected from H, C₁-C₆ alkyl and halogen, or is absent        when there is a double bond between C₁ and C₁₀;    -   R¹³ is selected from H and C₁-C₆ alkyl;    -   R¹⁶ is selected from H, C₁-C₆ alkyl and halogen; and    -   is a single or double bond.

In a further aspect, the invention is directed to an intermediatecompound of formula (IVc), or a solvate thereof

wherein

-   -   X represents H or it forms together with the carbon atom to        which it is bonded a ketone group or a ketone protecting group;    -   Z is selected from H and SiR′₃ wherein each R′ is independently        selected from C₁-C₆ alkyl and C₆-C₁₀ aryl;    -   R¹ is selected from H and SiR″₃, wherein each R″ is        independently selected from C₁-C₆ alkyl, C₆-C₁₀ aryl and        halogen;    -   R⁶ is selected from H, C₁-C₆ alkyl and halogen;    -   R¹⁰ is selected from H, C₁-C₆ alkyl and halogen, or is absent        when there is a double bond between C₁ and C₁₀;    -   R¹³ is selected from H and C₁-C₆ alkyl;    -   R¹⁶ is selected from H, C₁-C₆ alkyl and halogen; and    -   is a single or double bond.

DETAILED DESCRIPTION OF THE INVENTION

The term “alkyl” refers to a linear or branched alkane derivativecontaining from 1 to 6 (“C₁-C₆ alkyl”), preferably from 1 to 3 (“C₁-C₃alkyl”), carbon atoms and which is bound to the rest of the moleculethrough a single bond. Illustrative examples of alkyl groups includemethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl,hexyl.

The term “aryl” refers to an aromatic group having between 6 and 10,preferably 6 or 10 carbon atoms, comprising 1 or 2 aromatic nuclei boundthrough a carbon-carbon bond or fused to one another. Illustrativeexamples of aryl groups include phenyl, naphthyl, diphenyl, indenyl,phenanthryl, etc.

The term “halogen” refers to bromine, chlorine, iodine or fluorine.

The term “cycloalkyl” refers to a radical derived from cycloalkanecontaining from 3 to 7 (“C₃-C₇ cycloalkyl”), preferably from 3 to 6(“C₃-C₆ cycloalkyl”) carbon atoms. Illustrative examples of cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

“Heterocyclyl” refers to a stable cyclic radical of 3 to 10 members,preferably a cycle of 5 or 6 members consisting of carbon atoms and from1 to 5, preferably from 1 to 3, heteroatoms selected from nitrogen,oxygen and sulfur, and which may be completely or partially saturated orbe aromatic (“heteroaryl”). In the present invention, the heterocyclylcan be a mono-, bi- or tricyclic system which may include fused ringsystems. Illustrative examples of heterocyclyl groups include, forexample, pyrrolidine, piperidine, piperazine, morpholine,tetrahydrofuran, benzimidazole, benzothiazole, furan, pyrrole, pyridine,pyrimidine, thiazole, thiophene, imidazole, indole, etc.

The term “ketone protecting group”, as used herein, refers to a groupblocking the ketone function for subsequent reactions that can beremoved under controlled conditions. The use of ketone-protecting groupsis well known in the art for protecting groups against undesirablereaction during a synthetic procedure and such protecting groups areknown (e.g. T. H. Greene and P. G. M Wuts, Protective Groups in OrganicSynthesis, 4th edition, John Wiley & Sons, 2007). Virtually any ketoneprotecting group can be used to put the invention into practice.Illustrative, non-limiting examples of ketone protecting groups include:

-   -   acyclic ketals, dithioketals and hemithioketals

W can be oxygen or sulfur, and each R″′ can be independently selectedfrom C₁-C₆ alkyl and benzyl. Examples of acyclic ketals and dithioketalsinclude dimethyl ketal, diethyl ketal, diisopropyl ketal, dibutyl ketal,dibenzyl ketal, dimethyl thioketal, diethyl thioketal, diisopropylthioketal, dibutyl thioketal, dibenzyl thioketal;

-   -   cyclic ketals, dithioketals and hemithioketals

W can be oxygen or sulfur, n can be 0, 1 or 2, and each R″′ can beindependently selected from H and C₁-C₆ alkyl. Examples of cyclicketals, dithioketals and hemithioketals include 1,3-dioxolane,4-methyl-1,3-dioxolane, 4,5-dimethyl-1,3-dioxolane,4,4,5,5-tetramethyl-1,3-dioxolane, 1,3-dioxane, 4-methyl-1,3-dioxane,5-methyl-1,3-dioxane, 4,4-dimethyl-1,3-dioxane,5,5-dimethyl-1,3-dioxane, 4,5-dimethyl-1,3-dioxane,4,6-dimethyl-1,3-dioxane, 1,3-dioxapane, 1,3-dithiolane, 1,3-dithiane,1,3-oxathiolane;

-   -   enol ethers [C—X═C—O—R″′], in which case there would        additionally be a double bond between C₂ and C₃ or between C₃        and C₄. R″′ can be selected from C₁-C₆ alkyl and benzyl.        Examples of enol ethers include methyl enol ether, ethyl enol        ether, propyl enol ether, butyl enol ether, benzyl enol ether;    -   enamines

in which case there would additionally be a double bond between C₂ andC₃ or between C₃ and C₄. Each R″′ can be independently selected fromC₁-C₆ alkyl and benzyl, or the two R″′ groups together with the nitrogenatom to which they are bonded form a 5- or 6-membered heterocyclic ring.Examples of enamines include dimethyl enamine, diethyl enamine, dipropylenamine, dibutyl enamine, diallyl enamine, pyrrolidyne enamine,piperidyne enamine, morpholyne enamine;

-   -   oximes

R″′ can be selected from H, C₁-C₆ alkyl and benzyl. Examples of oximesinclude oxime, O-methyl oxime, O-benzyl oxime, O-phenylthiomethyl oxime;and

-   -   hydrazones

Each R″′ can be independently selected from H, C₁-C₆ alkyl, C₆-C₁₀ aryland benzyl. Examples of hydrazones include hydrazone, N,N-dimethylhydrazone, phenylhydrazone, 2,4-dinitrophenylhydrazone, tosylhydrazone.

The term “solvate” according to this invention is to be understood asmeaning any form of the compound which has another molecule (most likelya polar solvent) attached to it via non-covalent bonding. Examples ofsolvate include hydrates and alcoholates, e.g. methanolates.

The term “organic solvent” includes for example cyclic and acyclicethers (e.g. Et₂O, iPr₂O, MeOtBu, 1,4-dioxane, tetrahydrofuran,methyltetrahydrofuran), hydrocarbon solvents (e.g. pentane, hexane,heptane), halogenated solvents (e.g. dichloromethane, chloroform),aromatic solvents (e.g. toluene), esters (e.g. EtOAc), nitriles (e.g.acetonitrile), amides (e.g. DMF), alcohols (e.g. methanol, ethanol,propanol), sulfoxides (DMSO) and mixtures thereof.

In a first aspect, the invention is directed to a process for thepreparation of a compound of formula (I), or a solvate thereof

wherein X, Y, R⁶, R¹⁰, R¹³, R¹⁶ and

are as defined above,which comprises reacting a compound of formula (II) or a solvate thereof

with a compound of formula (III)

wherein

-   -   Z is selected from H and SiR′₃, wherein each R′ is independently        selected from C₁-C₆ alkyl and C₆-C₁₀ aryl; and    -   M is selected from Li, MgBr, MgCl and Mgl.

In a particular embodiment, R⁶, R¹⁰ and R¹⁶ are H.

In another embodiment, R¹³ is C₁-C₆ alkyl, preferably ethyl.

In another embodiment, R⁶, R¹⁰ and R¹⁶ are H and R¹³ is ethyl.Preferably, the compound of formula (I) or (II) is a compound of formula(Ia) or (IIa), or a solvate thereof.

In a particular embodiment, X is H. In another embodiment, X formstogether with the carbon atom to which it is bonded a ketone protectinggroup.

In a particular embodiment, the ketone protecting group is selected fromcyclic or acyclic ketals, cyclic or acyclic dithioketals, cyclic oracyclic hemithioketals, enol ethers, enamines, oximes and hydrazones.Preferably, the ketone protecting group is selected from cyclic ketals,cyclic dithioketals, cyclic hemithioketals, enol ethers and enamines. Inan embodiment, X forms together with the carbon atom to which it isbonded a group selected from:

wherein each W is independently selected from O and S; n is 0, 1 or 2;and

each R″′ is independently selected from H and C₁-C₆ alkyl;

ii) C—O—R″′, in which case there is additionally a double bond betweenC₂ and C₃ or between C₃ and C₄,

wherein R″′ is selected from C₁-C₆ alkyl and benzyl; and

in which case there would additionally be a double bond between C₂ andC₃ or between C₃ and C₄,

wherein each R″′ is independently selected from C₁-C₆ alkyl and benzyl,or the two R″′ groups together with the nitrogen atom to which they areattached form a 5- or 6-membered heterocyclic ring.

In a particular embodiment, X forms together with the carbon atom towhich it is bonded a group selected from:

wherein each W is independently selected from O and S; n is 0; and eachR″′ is independently selected from H and C₁-C₆ alkyl;

ii) C—O—R″′, in which case there is additionally a double bond betweenC₂ and C₃ or between C₃ and C₄, wherein R″′ is selected from C₁-C₆alkyl; and

in which case there would additionally be a double bond between C₂ andC₃ or between C₃ and C₄, wherein the two R″′ groups together with thenitrogen atom to which they are attached form a 5- or 6-memberedheterocyclic ring.

In an embodiment, X forms together with the carbon atom to which it isbonded a group selected from 1,3-dioxolane, 1,3-dithiolane, methyl enolether, ethyl enol ether and pyrrolidine enamine.

In a further embodiment, X forms together with the carbon atom to whichit is bonded a 1,3-dioxolane group and there is a double bond between C₅and C₆. In an embodiment, X forms together with the carbon atom to whichit is bonded a 1,3-dithiolane group and there is a double bond betweenC₄ and C₅. In an embodiment, X forms together with the carbon atom towhich it is bonded a methyl enol ether and there is a double bondbetween C₂ and C₃ and between C₅ and C₁₀. In an embodiment, X formstogether with the carbon atom to which it is bonded an ethyl enol etherand there is a double bond between C₃ and C₄ and between C₅ and C₆. Inan embodiment, X forms together with the carbon atom to which it isbonded a pyrrolidine enamine and there is a double bond between C₃ andC₄ and between C₅ and C₁₀.

In a particular embodiment, Y forms together with the carbon atom towhich it is bonded a C═CH₂ group. In another embodiment, Y formstogether with the carbon atom to which it is bonded a C(OH)CH₂Z group.

In an embodiment Z is H.

In another embodiment, Z is SiR′₃ wherein each R′ is independentlyselected from C₁-C₆ alkyl and C₁-C₆ aryl (Peterson olefinationreaction).

Preferably, each R′ is independently selected from methyl, ethyl,n-propyl, i-propyl, n-butyl, t-butyl, n-hexyl and phenyl. In anembodiment, Z is selected from Me₃Si—, Et₃Si—, ^(n)Pr₃Si—, ^(n)Pr₃Si—,^(n)Hex₃Si—, ^(t)Bu₃Si—, Ph₃Si—, MeEt₂Si—, ^(t)BuMe₂Si—, ^(t)BuPh₂Si—,MePh₂Si—, EtMe₂Si— and PhMe₂Si—. More preferably, Z is Me₃Si—.

In an embodiment of the invention, M is selected from Li and MgCl.Preferably, M is Li. In a particular embodiment, the compound of formula(III) is Me₃Si—CH₂—Li.

Reaction of the compound of formula (II) with the compound of formula(III) is preferably performed in the presence of an organic solvent,preferably, an anhydrous organic solvent, such as for example a cyclicor acyclic ether (e.g. Et₂O, iPr₂O, tBuOMe, 1,4-dioxane,tetrahydrofuran, methyltetrahydrofuran), a hydrocarbonated solvent (e.g.pentane, hexane, heptane), a halogenated solvent (e.g. dichloromethane,chloroform), an aromatic solvent (e.g. toluene) or mixtures thereof.Preferably the organic solvent is a cyclic or acyclic ether, such asEt₂O, iPr₂O, tBuOMe, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuranor mixtures thereof. In a particular embodiment, the organic solvent istetrahydrofuran. In the present document, the term anhydrous solventrefers to a solvent containing less than 500 ppm of water.

In a particular embodiment, this reaction is performed at a temperaturebetween −75° C. and the reflux temperature of the solvent used. In anembodiment, it is performed at a temperature of between −60° C. and 40°C., preferably between −60° C. and 25° C.

In a particular embodiment, the compound of formula (III) is present inan amount of from 1.0 to 6.0 molar equivalents with respect to thecompound of formula (II), preferably from 2.0 to 4.0 molar equivalents.

The process of the invention allows selective addition of the compoundof formula (III) to the keto group at position 11 of the compound offormula (II). Preferably, the reaction of the compound of formula (II)or a solvate thereof with the compound of formula (III) gives rise tothe compound of formula (I) or a solvate thereof with a selectivityhigher than 70%, preferably higher than 80%, preferably higher than 90%,more preferably higher than 95%, even more preferably higher than 98%(molar), with respect to the total addition products.

After reaction of the compound of formula (II), or a solvate thereof,with the compound of formula (III), a compound of formula (I) wherein Y,together with the carbon atom to which it is bonded, forms a C(OH)CH₂Zgroup is obtained. Said compound can be isolated and used in asubsequent step of the synthesis (e.g. ethynylation, Petersonelimination, dehydration) or it can be directly treated with an acid ora base in a one-pot process to afford a compound of formula (I) whereinY, together with the carbon atom to which it is bonded, representsC═CH₂. Therefore, in a particular embodiment, the process of theinvention comprises:

-   -   (a) reacting a compound of formula (II), or a solvate thereof,        with a compound of formula (III) to obtain a compound of formula        (I), or a solvate thereof, wherein Y together with the carbon        atom to which it is bonded represents a C(OH)CH₂Z group, wherein        Z is selected from H and SiR′₃, wherein each R′ is independently        selected from C₁-C₆ alkyl and C₆-C₁₀ aryl; and    -   (b) treating a compound of formula (I), or a solvate thereof,        wherein Y together with the carbon atom to which it is bonded        represents a C(OH)CH2Z group, wherein Z is selected from H and        SiR′₃, wherein each R′ is independently selected from C₁-C₆        alkyl and C₆-C₁₀ aryl, with an acid or a base to obtain a        compound of formula (I), or a solvate thereof, wherein Y        together with the carbon atom to which it is bonded represents        C═CH₂.        Ethynylation Reaction (Position 17)

The compound of formula (I), or a solvate thereof, can be furtherethynylated to obtain a compound of formula (IV), or a solvate thereof,

wherein

-   -   Y, R⁶, R¹⁰, R¹³, R¹⁶ and        are as defined above;    -   X represents H or it forms together with the carbon atom to        which it is bonded a ketone group or a ketone protecting group;        and    -   R¹ is selected from H and SiR″₃, wherein each R″ is        independently selected from C₁-C₆ alkyl, C₆-C₁₀ aryl and        halogen.

The ethynylation reaction can be performed either before or aftergenerating the C═CH₂ group at position 11 of the steroid. Hence, in aparticular embodiment, the process of the invention comprises:

-   -   (a) reacting a compound of formula (II), or a solvate thereof,        with a compound of formula (III) to obtain a compound of formula        (I), or a solvate thereof, wherein Y together with the carbon        atom to which it is bonded represents a C(OH)CH₂Z group;    -   (b) treating a compound of formula (I), or a solvate thereof,        wherein Y together with the carbon atom to which it is bonded        represents a C(OH)CH₂Z group, with an acid or a base to obtain a        compound of formula (I), or a solvate thereof, wherein Y        together with the carbon atom to which it is bonded represents        C═CH₂; and    -   (c) ethynylating a compound of formula (I), or a solvate        thereof, wherein Y together with the carbon atom to which it is        bonded represents C═CH₂, to obtain a compound of formula (IV),        or a solvate thereof, wherein Y together with the carbon atom to        which it is bonded represents C═C H₂.

In another embodiment, the process of the invention comprises:

-   -   (a) reacting a compound of formula (II), or a solvate thereof,        with a compound of formula (III) to obtain a compound of formula        (I), or a solvate thereof, wherein Y together with the carbon        atom to which it is bonded represents a C(OH)CH₂Z group;    -   (b) ethynylating a compound of formula (I), or a solvate        thereof, wherein Y together with the carbon atom to which it is        bonded represents a C(OH)CH₂Z group, to obtain a compound of        formula (IV), or a solvate thereof, wherein Y together with the        carbon atom to which it is bonded represents a C(OH)CH₂Z group;        and    -   (c) treating a compound of formula (IV), or a solvate thereof,        wherein Y together with the carbon atom to which it is bonded        represents a C(OH)CH₂Z group, with an acid or a base to obtain a        compound of formula (IV), or a solvate thereof, wherein Y        together with the carbon atom to which it is bonded represents        C═CH₂.

The ethynylation reaction can be performed under reaction conditionsdisclosed in the prior art for the alkynylation of steroids. In aparticular embodiment, the ethynylation reaction is carried out bytreating the compound of formula (I), or a solvate thereof, with acompound of formula (V)

wherein

-   -   M′ is selected from Li, Na, K, MgBr, MgCl and Mgl; and    -   R¹ is selected from H and SiR″₃, wherein each R″ is        independently selected from C₁-C₆ alkyl, C₆-C₁₀ aryl and        halogen.

In a particular embodiment, each R″ is independently selected from C₁-C₆alkyl, phenyl and Cl. In a further embodiment, each R″ is independentlyselected from methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl,n-hexyl, Ph and Cl. Preferably, −SiR″₃ is selected from Et₃Si−, Me₃Si−,^(i)Pr₃Si—, ^(n)Pr₃Si—, ^(n)Hex₃Si−, ^(t)Bu₃Si—, Ph₃Si—, Cl₃Si—,MeEt₂Si—, ^(t)BuMe₂Si—, ^(t)BuPh₂Si—, Cl^(i)Pr₂Si—, ClMe₂Si—, MePh₂Si—,EtMe₂Si—, EtCl₂Si—, MeCl₂Si—, PhMe₂Si— and PhMeClSi—. More preferably,—SiR″₃ is selected from Me₃Si—, Et₃Si—, ^(i)Pr₃Si—, PhMe₂Si—,^(t)BuMe₂Si— and ^(t)BuPh₂Si—. Still more preferably, —SiR″₃ is Me₃Si—.

In an embodiment, R¹ is H.

In a preferred embodiment, R¹ is a SiR″₃ group. Preferably, R¹ is aSiR″₃ group wherein each R″ is independently selected from C₁-C₆ alkyl,such as SiMe₃.

In an embodiment, M′ is Li. Preferably, M′ is Li and R¹ is a SiR″₃group.

In another embodiment, M′ is selected from MgBr, MgCl and Mgl.Preferably, M′ is selected from MgBr, MgCl and Mgl and R¹ is H.

The ethynylation reaction is preferably performed in the presence of anorganic solvent, preferably, an anhydrous organic solvent, such as forexample a cyclic or acyclic ether (e.g. Et₂O, iPr₂O, 1,4-dioxane,tetrahydrofuran, methyltetrahydrofuran), a hydrocarbon solvent (e.g.pentane, hexane, heptane), a halogenated solvent (e.g. dichloromethane,chloroform), an aromatic solvent (e.g. toluene) or mixtures thereof.Preferably the organic solvent is a cyclic or acyclic ether, such asEt₂O, iPr₂O, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran; ahydrocarbon solvent, such as pentane, hexane, heptane; or mixturesthereof.

In a particular embodiment, this reaction is performed at a temperaturebetween −75° C. and the reflux temperature of the solvent used. In anembodiment, it is performed at a temperature of between −60° C. and 50°C., preferably between −30° C. and 30° C.

In a particular embodiment, the compound of formula (V) is present in anamount of from 1.0 to 5.0 molar equivalents with respect to the compoundof formula (I), preferably from 1.1 to 3.0 molar equivalents.

When X in the compound of formula (I), or a solvate thereof, formstogether with the carbon atom to which it is bonded a ketone protectinggroup, depending on the ethynylation reaction conditions, the ketoneprotecting group and/or the acid or based used to generate the C═CH₂group at position 11, then a compound of formula (IV), or a solvatethereof, wherein X forms, together with the carbon atom to which it isbonded, a ketone protecting group or a ketone group can be obtained.

In an embodiment of the invention, a compound of formula (IV), or asolvate thereof, wherein X forms, together with the carbon atom to whichit is bonded, a ketone protecting group is maintained after theethynylation reaction.

In a particular embodiment, a compound of formula (IV), or a solvatethereof, wherein X forms, together with the carbon atom to which it isbonded, a ketone group is obtained after treating the compound offormula (IV), or a solvate thereof, with an acid or a base to generatethe C═C H₂ group.

When R¹ is a SiR″₃ group, desilylation can be performed to obtain acompound of formula (IV), or a solvate thereof, wherein R¹ is H.

This desylilation reaction can be carried out by methods known in theprior art (e.g. T. H. Greene and P. G. M Wuts, Protective Groups inOrganic Synthesis, 4^(th) edition, John Wiley & Sons, 2007). In aparticular embodiment, the desilylation is carried out using fluorinesalts or bases in the presence of water, an organic solvent or mixturesthereof. Fluorine salts such as pyridinium fluoride, potassium fluorideor ammonium fluoride; or inorganic bases, such as sodium hydroxide,lithium hydroxide, potassium hydroxide or potassium carbonate can beused. In a particular embodiment, the desilylation reaction is carriedout in the presence of an inorganic base and an organic solvent.

In a particular embodiment, the desilylation reaction is performed at atemperature between −60 and +100° C. In another embodiment, it isperformed at a temperature between −10 and +60° C., preferably between10 and 35° C.

Desilylation reaction can be performed either before or after thegeneration of the C═CH₂ group at position 11 and either before or aftercleavage of the ketone protecting group.

Generation of the C═CH₂ Group (Position 11)

In an embodiment, a compound of formula (I), or a compound of formula(IV), or a solvate thereof, wherein Y together with the carbon atom towhich it is bonded represents a C(OH)CH₂Z group, is treated with an acidor a base to obtain a compound of formula (I), or a compound of formula(IV), or a solvate thereof, wherein Y together with the carbon atom towhich it is bonded represents C═CH₂.

When Z is a SiR′₃ group, treatment with an acid or a base gives rise toa compound wherein Y together with the carbon atom to which it is bondedrepresents C═CH₂ (Peterson elimination reaction).

When Z is H, treatment with an acid gives rise to a compound wherein Ytogether with the carbon atom to which it is bonded represents C═CH₂(dehydration reaction).

Suitable acids include organic acids, inorganic acids, Lewis acids andmixtures thereof. Examples of suitable acids include acetic acid,trifluoroacetic acid, chloroacetic acid, methanesulfonic acid,trifluoromethanesulfonic acid, formic acid, propionic acid, butyricacid, malic acid, citric acid, benzoic acid, p-toluenesulfonic acid,oxalic acid, succinic acid, hydrochloric acid, hydrobromic acid,hydrofluoric acid, perchloric acid, chloric acid, sulfuric acid, nitricacid, phosphoric acid, ZnCl₂, AlCl₃ and BF₃. In a particular embodiment,the acid is selected from acetic acid, trifluoroacetic acid,methanesulfonic acid, trifluoromethanesulfonic acid, hydrochloric acid,hydrobromic acid, perchloric acid, sulfuric acid and mixtures thereof.

Suitable bases include e.g. alkali metal hydrides, alkali metalalkoxides, alkali metal hydroxides, such as sodium hydride, potassiumhydride, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassiummethoxide, potassium ethoxide, potassium t-butoxide, sodium hydroxideand potassium hydroxide.

In a particular embodiment, a compound of formula (I), or a solvatethereof, wherein Y together with the carbon atom to which it is bondedrepresents a C(OH)CH₂Z group, is treated with an acid or a base beforethe ethynylation reaction to afford a compound of formula (I), or asolvate thereof, wherein Y together with the carbon atom to which it isbonded represents C═CH₂.

In another embodiment, treatment with an acid or a base is performedafter the ethynylation reaction so that a compound of formula (IV), or asolvate thereof, wherein Y together with the carbon atom to which it isbonded represents a C(OH)CH₂Z group, is converted into a compound offormula (IV), or a solvate thereof, wherein Y together with the carbonatom to which it is bonded represents C═CH₂. In this case, depending onthe acid or base employed, the reaction conditions and/or the ketoneprotecting group, a compound of formula (IV), or a solvate thereof,wherein X forms, together with the carbon atom to which it is bonded, aketone protecting group or a ketone group can be obtained.

In a preferred embodiment, the acid or based used to generate the C═CH₂group at position 11 also allow cleavage of the ketone protecting groupat position 3 so that it is obtained a compound of formula (IV) whereinY, together with the carbon atom to which it is bonded, represents C═CH₂and X, together with the carbon atom to which it is bonded, represents aketone group.

Cleavage of the Ketone Protecting Group (Position 3)

In order to obtain a compound of formula (IV) wherein X is hydrogen orforms, together with the carbon atom to which it is bonded, a ketonegroup, a deprotection step of the ketone protecting group may be needed.Cleavage of the ketone protecting group can be carried out by anyconventional means known in the art (e.g. T. H. Greene and P. G. M Wuts,Protective Groups in Organic Synthesis, 4^(th) edition, John Wiley &Sons, 2007).

For example, when the ketone protecting group is a ketal, a thioketal oran enol ether, it can be cleaved to regenerate de 3-keto group in acidmedia.

When the ketone protecting group is an enamine, it can be cleaved byhydrolysis in acid or basic media according to well establishedprocedures of the state of the art.

When the ketone protecting group is a dithioketal, it can be cleaved byoxidation or in the presence of a Lewis acid. In addition, when theketone protecting group is a dithioketal it can be removed underreducing conditions to obtain a compound wherein X is H.

In a particular embodiment, the ketone protecting group is cleaved underthe reactions conditions employed to generate the CH═CH₂ group atposition 11, so that both processes occur in a single step.

In view of the information provided herein, the skilled person willappreciate that different sequences of steps can be used and thatfurther synthetic steps might be needed to put the invention intopractice.

For example, to obtain a compound of formula (IV) wherein R¹ is H and Xis hydrogen or forms, together with the carbon atom to which it isbonded, a ketone group, it might be necessary to carry out one or bothof the following steps:

-   -   (i) cleavage of the ketone protecting group to afford a compound        of formula (IV), or a solvate thereof, wherein X is H or forms        together with the carbon atom to which it is bonded a ketone        group,    -   (ii) removal of the SiR″₃ group to afford a compound of formula        (IV), or a solvate thereof, wherein R¹ is H.

These steps can be carried out in any order. That is, if both steps arecarried out, step (i) can be carried out either before or after step(ii).

In order to convert a compound of formula (I), or a solvate thereof,wherein Y together with the carbon atom to which it is bonded representsa C(OH)CH₂Z, into a compound of formula (IV), or a solvate thereof,wherein R¹ is H, X forms together with the carbon atom to which it isbonded a ketone group and Y together with the carbon atom to which it isbonded represents CH═CH₂, any of the following sequences of steps can befollowed:

-   -   ethynylation/generation of the CH═CH₂ group/if needed,        desilylation of the alkyne/if needed, cleavage of the ketone        protecting group; or    -   ethynylation/generation of the CH═CH₂ group/if needed, cleavage        of the ketone protecting group/if needed, desilylation of the        alkyne; or    -   ethynylation/if needed, desilylation of the alkyne/generation of        the CH═CH₂ group/if needed, cleavage of the ketone protecting        group; or    -   ethynylation/generation of the CH═CH₂ group/if needed,        desilylation of the alkyne/if needed, cleavage of the ketone        protecting group; or    -   generation of the CH═CH₂ group/ethynylation/if needed,        desilylation of the alkyne/if needed, cleavage of the ketone        protecting group; or    -   generation of the CH═CH₂ group/ethynylation/if needed, cleavage        of the ketone protecting group/if needed, desilylation of the        alkyne; or    -   ethynylation/if needed, cleavage of the ketone protecting        group/generation of the CH═CH₂ group/if needed, desilylation of        the alkyne; or    -   ethynylation/if needed, cleavage of the ketone protecting        group/if needed, desilylation of the alkyne/generation of the        CH═CH₂ group.

In order to convert a compound of formula (I), or a solvate thereof,wherein Y together with the carbon atom to which it is bonded representsa C(OH)CH₂Z, into a compound of formula (IV), or a solvate thereof,wherein R¹ is H, X is hydrogen and Y together with the carbon atom towhich it is bonded represents CH═CH₂, any of the following sequences ofsteps can be followed:

-   -   ethynylation/generation of the CH═CH₂ group/if needed,        desilylation of the alkyne/if needed, reductive elimination of        the ketone protecting group; or    -   ethynylation/generation of the CH═CH₂ group/if needed, reductive        elimination of the ketone protecting group/if needed,        desilylation of the alkyne; or    -   ethynylation/if needed, desilylation of the alkyne/generation of        the CH═CH₂ group/if needed, reductive elimination of the ketone        protecting group; or    -   ethynylation/generation of the CH═CH₂ group/if needed,        desilylation of the alkyne/if needed, reductive elimination of        the ketone protecting group; or    -   generation of the CH═CH₂ group/ethynylation/if needed,        desilylation of the alkyne/if needed, reductive elimination of        the ketone protecting group; or    -   generation of the CH═CH₂ group/ethynylation/if needed, reductive        elimination of the ketone protecting group/if needed,        desilylation of the alkyne; or    -   ethynylation/if needed, reductive elimination of the ketone        protecting group/generation of the CH═CH₂ group/if needed,        desilylation of the alkyne; or    -   ethynylation/if needed, reductive elimination of the ketone        protecting group/if needed, desilylation of the        alkyne/generation of the CH═CH₂ group.        Synthesis of Etonooestrel and Desooestrel

Compounds of formula (I) obtained by the process of the invention areuseful intermediates in the preparation of several pharmaceuticallyactive agents, such as e.g. Etonogestrel and Desogestrel.

In a further aspect, the invention is directed to a process for thepreparation of Etonogestrel, or Desogestrel, or a solvate thereof, whichcomprises reacting a compound of formula (II), or a solvate thereof, asdefined herein with a compound of formula (III) as defined herein.

In a particular embodiment, Etonogestrel can be obtained by a processwhich comprises:

-   -   (a) reacting a compound of formula (IIa), or a solvate thereof,

-   -   -   wherein X forms together with the carbon atom to which it is            bonded a ketone protecting group;        -   with a compound of formula (III)

-   -   -   wherein            M and Z are as defined herein;        -   to afford a compound of formula (Ia-1) or a solvate thereof

-   -   (b) treating a compound of formula (Ia-1), or a solvate thereof,        with an acid or a base to afford a compound of formula (Ia-2),        or a solvate thereof,

-   -   (c) ethynylating a compound of formula (Ia-2), or a solvate        thereof, to afford a compound of formula (IVa-1), or a solvate        thereof

-   -   -   wherein            -   X forms together with the carbon atom to which it is                bonded a ketone group or a ketone protecting group            -   R¹ is selected from H and SiR″₃, wherein each R″ is                independently selected from C₁-C₆ alkyl, C₆-C₁₀ aryl and                halogen; and

    -   (d) if necessary, carrying out one or both of the following        steps in any order:        -   (i) if X forms together with the carbon atom to which it is            bonded a ketone protecting group, cleavage of the ketone            protecting group to afford a compound of formula (IVa-1), or            a solvate thereof, wherein X forms together with the carbon            atom to which it is bonded a ketone group,        -   (ii) if R¹ is a SiR″₃ group, removal of the SiR″₃ group to            afford a compound of formula (IVa-1), or a solvate thereof,            wherein R¹ is H.

In another embodiment, Etonogestrel can be obtained by a process whichcomprises:

-   -   (a) reacting a compound of formula (IIa), or a solvate thereof,

-   -   -   wherein X forms together with the carbon atom to which it is            bonded a ketone protecting group;        -   with a compound of formula (III)

-   -   -   wherein            , M and Z are as defined herein;        -   to afford a compound of formula (Ia-1), or a solvate            thereof,

-   -   (b) ethynylating a compound of formula (Ia-1), or a solvate        thereof, to afford a compound of formula (IVa-2), or a solvate        thereof

-   -   -   wherein R¹ is selected from H and SiR″₃, wherein each R″ is            independently selected from C₁-C₆ alkyl, C₆-C₁₀ aryl and            halogen;

    -   (c) treating a compound of formula (IVa-2), or a solvate        thereof, with an acid or a base to afford a compound of formula        (IVa-1), or a solvate thereof

-   -   -   wherein            -   X forms together with the carbon atom to which it is                bonded a ketone group or a ketone protecting group            -   R¹ is selected from H and SiR″₃, wherein each R″ is                independently selected from C₁-C₆ alkyl, C₆-C₁₀ aryl and                halogen; and

    -   (d) if necessary, carrying out one or both of the following        steps in any order:        -   (i) if X forms together with the carbon atom to which it is            bonded a ketone protecting group, cleavage of the ketone            protecting group to afford a compound of formula (IVa-1), or            a solvate thereof, wherein X forms together with the carbon            atom to which it is bonded a ketone group,        -   (ii) if R¹ is a SiR″₃ group, removal of the SiR″₃ group to            afford a compound of formula (IVa-1), or a solvate thereof,            wherein R¹ is H.

In another embodiment, Desogestrel can be obtained by a process whichcomprises:

-   -   (a) obtaining a compound of formula (IVa-1), or a solvate        thereof, by any of the processes defined above wherein X forms        together with the carbon atom to which it is bonded a cyclic        dithioketal group;        -   (b) cleavage of the cyclic dithioketal group under reducing            conditions to obtain a compound of formula (IVb-1), or a            solvate thereof; and        -   (c) if R¹ is a SiR″₃ group, removal of the SiR″₃ group to            afford a compound of formula (IVb-1), or a solvate thereof,            wherein R¹ is H, either before or after step (b).

In a further embodiment of the invention, Desogestrel can be obtained bya process comprising:

-   -   (a) reacting compound (12), or a solvate thereof,

-   -   -   with a compound of formula (III)

-   -   -   wherein M and Z are as defined herein;        -   to afford a compound of formula (Ib-1) or a solvate thereof

-   -   (b) treating a compound of formula (Ib-1), or a solvate thereof,        with an acid or a base to afford a compound of formula (Ib-2),        or a solvate thereof,

-   -   (c) ethynylating a compound of formula (Ib-2), or a solvate        thereof, to afford a compound of formula (IVb-1), or a solvate        thereof

-   -   -   wherein R¹ is selected from H and SiR″₃, wherein each R″ is            independently selected from C₁-C₆ alkyl, C₆-C₁₀ aryl and            halogen; and

    -   (d) if R¹ is a SiR″₃ group, removing SiR″₃ group to afford        Desogestrel, or a solvate thereof.        Compounds of Formula (Ic) and (IVc)

In another aspect, the invention is directed to a compound of formula(Ic), or a solvate thereof,

wherein X, Z, R⁶, R¹⁰, R¹³, R¹⁶ and

are as defined herein.

Preferred embodiments for X, Z, R⁶, R¹⁰, R¹³, R¹⁶ and

are as defined above.

In a particularly preferred embodiment, in the compound of formula (Ic)Z is SiR′₃ wherein each R′ is independently selected from C₁-C₆ alkyland C₆-C₁₀ aryl. Preferred embodiments for R′ are as defined above.

In another particular embodiment, the compound of formula (Ic) does notrepresent:

(11α-methyl-3-(N-pyrrolidyl)-Δ^(3,5)-androstadien-11β-ol-17-one),

(11α-methyl-Δ⁵-androsten-11β-ol-3,17-dione-3-monoethylene ketal), or

(11α-methyl-11β-hydroxy-Δ⁴-estren-17-one).

In a particular embodiment, the compound of formula (Ic) is a compoundof formula (Ia-1), or a compound of formula (Ib-1), or a solvatethereof.

In a preferred embodiment, the compound of formula (Ic) is selectedfrom:

-   -   or a solvate thereof.

In another aspect, the invention is directed to a compound of formula(IVc), or a solvate thereof,

wherein X, Z, R¹, R⁶, R¹⁰, R¹³, R¹⁶ and

are as defined herein.

Preferred embodiments for X, Z, R¹, R⁶, R¹⁰, R¹³, R¹⁶ and

are as defined above.

In a particularly preferred embodiment, in the compound of formula (IVc)R¹ is SiR″₃, wherein each R″ is independently selected from C₁-C₆ alkyl,C₆-C₁₀ aryl and halogen. Preferred embodiments for R″ are as definedabove.

In a particular embodiment, the compound of formula (IVc) does notrepresent:

(4-androsten-11α-methyl-11β, 17β-diol-17α-ethynyl-3-one),

(5-androsten-11α-methyl-11β, 17β-dio17α-ethynyl-3-one ethyleneketal),

(18,19-dinorpregn-5-en-20-yn-3-one, 13-ethyl-11,17β-dihydroxy-11-methyl,cyclic 1,2-ethanediylacetal), or

(18,19-dinorpregn-4-en-20-yn-3-one,13-ethyl-11,17β-dihydroxy-11-methyl).

In a particular embodiment, the compound of formula (IVc) is a compoundof formula (IVa-2), or a compound of formula (IVb-2), or a solvatethereof.

In a preferred embodiment, the compound of formula (IVc) is selectedfrom:

or a solvate thereof.

It should be understood that the scope of the present disclosureincludes all the possible combinations of embodiments disclosed herein.

The following examples illustrate the invention and should not beconsidered as limitative of the invention.

EXAMPLES Example 1 Synthesis of 18-methyl-estra-4-en-3,11,17-trione(2—Swern Oxidation)

Oxalyl chloride was added to 540 mL of DCM at −20° C. The solution wascooled down at −45° C. and then DMSO (63 mL) diluted in 450 mL of DCMwas dropwise added keeping the temperature below −35° C. After additionwas complete, the reaction mixture was stirred 20 min at −40° C. Then,45 g of compound 1 dissolved in 450 mL of DCM were then added keepingthe temperature below −35° C. The reaction mixture was kept at −40° C.for 30 min, then DIPEA (235 mL) was quickly added and the cold bathremoved allowing to warm up to room temperature (1.5 h). 675 mL of 3.3%solution of acetic acid were added and the aqueous phase was separated.The organic phase was washed with 315 mL of a solution of NaHCO₃ 7%,separated and concentrated under vacuum to a volume of 150 mL. 150 mL ofIPA were added and reduced the volume to 150 mL. The operation wasrepeated two more times to reach a final volume of 150 mL. The resultingsuspension was stirred in an ice bath for 30 min and then filtered, thesolid was washed with 45 mL of cold IPA and dried under vacuum at 40° C.39.8 g of compound 2 were obtained as white solid (yield=89.5%).

Example 2 Synthesis of 18-methyl-estra-4-en-3,11,17-trione(2—Parikh-Doering Oxidation)

15 g of compound 1 were dissolved in 40 mL of DMSO and then 71 mL of TEAwere added. The solution was heated at 30° C., and a solution of SO₃Py(79 g) in 70 mL of DMSO were added. The reaction mixture was stirred at30° C. for 3 h, and then poured over a solution of 117 mL of glacialacetic acid in 234 mL of water forming a precipitate. The suspension wascooled in an ice bath for 1 h, and filtered. The solid was suspended in80 mL of IPA and heated to complete dissolution and then cooled down at0° C. The resulting solid was filtered and dried under vacuum at 40° C.to yield 13 g of compound 2 (81%).

Example 3 Synthesis of Compound 3 (Ketone Protection)

18 g of compound 2 were dissolved in 140 mL of THF, then 30 mL of TEOFand 900 mg of pTsOH were added. The reaction mixture was stirred at 25°C. for 3 h. Then 2 mL of TEA were added, and 90 mL of solution of NaHCO₃7%. The aqueous phase was extracted with 50 mL EtOAc. The combinedorganic phases were concentrated until a wet solid was obtained, 90 mLof ethanol were added and concentrated to a volume of 40 mL, cooled inan ice bath and filtered. The solid was washed with 90 mL of coldethanol and dried under vacuum at 40° C., to yield 14.7 g of compound 3(75%).

Example 4 Synthesis of Compound 4 (Peterson Olefination)

10 g of compound 3 were dissolved in 50 mL of THF and cooled down at−40° C. Then 88 mL of trimethylsilyl methyl lithium were slowly added,keeping the temperature below −35° C., and the mixture stirred for 1 hfurther after addition was complete. Then 200 mL of solution of NaHCO₃7% were added, separated and the aqueous phase was extracted with 100 mLEtOAc. The combined organic phases were concentrated to 30 mL, 30 mL ofethanol were added and the solvent was evaporated to a final volume of30 mL. The operation was repeated two more times, then the suspensionwas cooled in an ice bath for 1h. The solid was filtered, washed with 10mL of cold ethanol and dried under vacuum at 40° C., to yield 10.4 g ofcompound 4 (83% yield).

¹H NMR (400 MHz, CDCl₃): δ 0.09 (s, 9H); 0.82 (t, 3H); 1.17-1.39 (m,10H); 1.63-1.66 (m, 1H); 1.68-1.72 (m, 1H); 1.84-1.87 (m, 2H); 1.92-2.12(m, 3H); 2.21-2.35 (d, 3H); 2.39-2.51 (m, 4H); 3.69-3.79(m, 2H); 5.19(s, 1H) 5.31 (d, 1H).

¹³C NMR (100 MHz, CDCl₃): δ 1.1; 8.4; 14.7; 18.5; 21.3; 29.2; 30.7;31.2; 35.1; 35.6; 37.1; 38.4; 43.4; 50.7; 51.5; 53.3; 62.4; 100.1;117.3; 137.8; 156.2; 218.8.

Example 5 Synthesis of Compound 5 (Ethynylation Reaction)

To a solution of hexillithium (76 mL) in heptane (100 mL) cooled at 0°C., a solution of trimethylsilyl acetylene (30 mL) in 100 ml of amixture of THF/heptanes ⅓ was slowly added. The reaction mixture wasstirred at 0° C. for 30 min, then a solution of compound 4 (10 g) in 100mL of THF was added and the mixture stirred for 1h further. Water (200mL) was added to quench the excess of lithium reagent and the organicphase concentrated under vacuum. The residue (containing 85% of compound5 and 15% of compound 4, maximum level of conversion obtained) waspurified on silica gel with EtOAc/heptanes 1/9, affording pure compound5 as an oil.

¹H NMR (400 MHz, CDCl₃): δ 0.07 (s, 9H); 0.12 (s, 9H) 0.83-0.85 (m, 1H);1.12-1.18 (m, 5H); 1.22-1.28 (m, 6H); 1.33-1.38 (m, 3H); 1.58-1.66 (m,4H); 1.91 (d, 1H); 1.98-2.09 (m, 3H); 2.17 (d, 1H); 2.27-2.36 (m, 4H);3.68-3.77(m, 2H); 5.18 (s, 1H) 5.29 (d, 1H).

¹³C (100 MHz, CDCl₃): δ 1.1; 8.4; 14.7; 18.5; 21.3; 29.2; 30.7; 31.2;35.1; 35.6; 37.1; 38.4; 43.4; 50.7; 51.5; 53.3; 62.4; 100.1; 117.3;137.8; 156.2; 218.8.

Example 6 Synthesis of Etonogestrel (Ethynylation Reaction)

1.9 g of compound 4 were dissolved in 19 mL of THF, cooled down at 0° C.and 30 mL of LaCl₃*2LiCl were added, followed by slow addition ofethynylmagnesium chloride (120 mL) keeping the temperature below 10° C.After 15 h, 2.5 mL of TEA and 250 mL of solution of NaHCO₃ 7% wereadded. The aqueous phase was extracted with EtOAc 50 mL×2, and thecombined organic phases were washed with brine. The solvent wasevaporated under reduced pressure to a volume of 20 mL and 40 mL ofmethanol were added. It was concentrated to 20 mL and repeated twice.The final methanol solution was treated with 2 mL of HCl, stirred at 25°C. for 1 h, and 2 mL of solution of NaHCO₃ ₇% were added. Addition of 1mL of water promoted the precipitation of a solid. It was filtered,washed with 4 mL of water and dried under vacuum at 40° C., yielding 2 gof crude Etonogestrel as brown solid (hplc purity 94%).

Example 7 Synthesis of Etonogestrel (One-Pot Ethynylation/Deprotection)

To a solution of hexillithium (65 mL) in heptane (100 mL) cooled at −5°C., a solution of trimethylsilyl acetylene (26 mL) in 100 ml of amixture of THF/heptanes ⅓ was slowly added. The reaction mixture wasstirred at −5° C. for 30 min, then a solution of compound 4 (10 g) in100 mL of THF/heptanes 1:1 was added and the mixture stirred for 15hfurther. Water (200 mL) was added to quench the excess of lithiumreagent and the organic phase concentrated under vacuum. The residue(containing 90% of compound 5 and 10% of compound 4) was dissolved in 50mL of methanol, 0.5 mL of HCl were added and stirred 1 h at 20° C.,followed by addition of 3 mL of NaOH 50% and stirring for 1 h further.The solvent was evaporated under reduced pressure, the residue dissolvedin 100 mL of DCM. It was washed first with a solution of glacial aceticacid 3% and then with a solution of NaHCO₃ 7%. The crude obtained wasdissolved in 30 mL of acetone, concentrated to a volume of 12 mL and 12mol of IPA were added with further reduction of the volume of 50%. Theoperation was repeated twice. The suspension was cooled in an ice bathand the solid filtered, washed with 4 mL of cold IPA and dried at 40° C.under vacuum, to yield 2.1 g of Etonogestrel.

Example 8 Synthesis of Compound 6 (Peterson Elimination/Deprotection)

The residue obtained following Example 5 was dissolved in 20 mL ofmethanol and 2 mL of solution of HCl were added. The reaction mixturewas stirred at 25° C. for 1 h, the solvent was then evaporated, 50 mL ofwater were added and the mixture extracted with 50 mL of EtOAc. Thecrude product was purified on silica gel with EtOAc/heptanes 1/9,affording pure compound 6 as a white solid.

Example 9 Synthesis of Compound 7 (TMS Deprotection)

The residue obtained following Example 5 was dissolved in 20 mL ofmethanol and 2 mL of solution of NaOH 30% were added. The reactionmixture was stirred at 25° C. for 1 h, the solvent was then evaporated,50 mL of water were added and the mixture extracted with 50 mL of EtOAc.The crude product was purified on silica gel with EtOAc/heptanes 1/9,affording pure compound 7 as an orange oil.

Example 10 Synthesis of Etonogestrel (TMS Deprotection)

1 g of compound 6 was dissolved in 10 mL of acetone and then distilledup to a volume of 4 mL. 4 mL of IPA were added and concentrated up to avolume of 4 mL. The operation was repeated three times. The solution wasthen cooled at 0° C., filtered and washed with 2 mL of IPA. The solidwas dried under vacuum to afford pure etonogestrel.

Example 11 Synthesis of Compound 8 (Ketone Protection)

Compound 2 (28 g) was dissolved in DCM (280 mL), then 14 mL of1,2-ethanedithiol and 1.4 g of pTsOH were added. The reaction mixturewas refluxed for 5 h, 50 mL of DCM were distilling every hour (andadding fresh solvent). 140 mL of solution of NaHCO₃ 7% were added andthe aqueous phase extracted with 50 mL of DCM. The combined organicphases were concentrated under vacuum to a final volume of 150 mL. 150mL of methanol were added and concentrated under reduced pressure to afinal volume of 100 mL. The obtained suspension was cooled in an icebath for 1 h. The resulting solid was filtered, washed with 25 mL ofcold methanol and dried under vacuum at 40° C., to yield 30 g ofcompound 8.

Example 12 Synthesis of Compound 9 (Peterson Olefination)

Compound 8 (20 g) was dissolved in THF (100 mL) and cooled at 0° C. Then640 mL of trimethylsilyl mehtyl lithium were slowly added, keeping thetemperature below 10° C. and the mixture was stirred for 1h furtherafter addition was complete. Then, 300 mL of solution of NaH₄Cl 12% wereadded, separated and the aqueous phase was extracted with 100 mL ofEtOAc. The combined organic phases were concentrated to a volume of 100mL and the suspension was cooled with an ice bath for 1h. The resultingsolid was filtered, washed with 30 mL of cold EtOAc and dried undervacuum at 40° C., to yield 11 g of compound 9 (43%).

Example 13 Synthesis of Compound 10 (Peterson Elimination)

11 g of compound 10 were dissolved in 35 mL of methanol and 0.5 ml ofHCl were added, the reaction mixture was stirred at 25° C. for 1 h.After adjusting the pH to 6 and adding TEA, the suspension was cooled inan ice bath. The resulting precipitate was filtered, washed with 10 mLof methanol and dried under vacuum at 40° C., affording 7.8 g ofcompound 11 (88%).

Example 14 Synthesis of Compound 11 (Ethynylation Reaction)

7.0 g of compound 10 were dissolved in 35 mL of THF, cooled down at 10°C. and 46 mL of LaCl₃*2LiCl were added, followed by slow addition ofethynylmagnesium chloride (159 mL) keeping the temperature below 15° C.After the addition was completed, the reaction mixture was heated for 2hat 30° C. Then cooled down at 5° C. and 150 mL of a solution 10% HClwere added. The aqueous phase was extracted with 50 mL of EtOAc, and thecombined organic phases were washed with brine. The solvent wasevaporated under reduced pressure to a volume of 40 mL and 40 mL ofheptane were added. It was concentrated to 40 mL and repeated twice. Theobtained suspension was cooled in an ice bath for 1 h. The solid wasfiltered, washed with 10 mL of cold heptane and dried under vacuum at40° C., to yield 5.8 g of compound 11 (77%).

Example 15 Synthesis of Etonoqestrel (Ketone Deprotection)

Thioacetal was removed using periodic acid, as described in example 8Ain WO 2013/135744, or using SIBX as described in example 8C in WO2013/135744.

Example 16 Synthesis of Compound 14 (Peterson Olefination)

Compound 12 (10 g) was dissolved in THF (50 mL) and cooled at 0° C.Then, 330 mL of trimethylsilyl methyl lithium were slowly added, keepingthe temperature below 10° C. and the mixture stirred for 1.5 h furtherafter addition was complete. Then, 150 mL of solution of NaH₄Cl 12% wereadded, separated and the aqueous phase was extracted with 50 mL EtOAc.The combined organic phases were concentrated to a volume of 20 mL, andthe suspension was cooled with an ice bath for 1 h. The resulting solidwas filtered, dissolved in 20 mL of methanol, and 0.25 ml of HCl wereadded. The reaction mixture was stirred at 25° C. for 1.5 h. Afteradjusting the pH to 6 and adding TEA, the suspension was cooled in anice bath. The precipitate was filtered, washed with 5 mL of methanol anddried under vacuum at 40° C., affording 7.6 g of compound 14 (76%).

Example 17 Synthesis of Desogestrel (Ethynylation Reaction)

To a solution of hexillithium (3.0 g 2.3 M in hexane) in hexane (5 mL)cooled at −5° C., a solution of trimethylsilyl acetylene (1.32 g) in 6.8mL of a mixture of THF/hexane 1/7 was slowly added. The reaction mixturewas stirred at −5° C. for 30 min, then a solution of compound 14 (1.0 g)in 8 mL of hexane was added and the mixture stirred for 1 h at 0/5° C.Aqueous NaCl solution (8.5 mL) was added and the phases were separated.The organic phase was mixed with 5 mL of methanol, followed by additionof 1.5 mL of aqueous NaOH 30% and stirred for 4 h further. 10 mL of anaqueous solution of 3% Acetic acid was added. The phases were separatedand the organic phase was washed with water (5.0 mL). The solvent wasevaporated under reduced pressure and the residue dissolved in 1 mL ofMeOH. The solvent was evaporated under reduced pressure and the residuedissolved in 2 mL of Hexane. The crude obtained was dissolved in 4 mL ofhexane by heating at 60° C. The solution was cooled slowly in an icebath and the resulting solid filtered, washed with 1 mL of cold hexaneand dried at 40° C. under vacuum, to yield 0.89 g of Desogestrel (89%).

Example 18 Synthesis of Compound 15 (Methylation)

200 mg of compound 3 were dissolved in 1.0 mL of THF. Then 1.0 mL ofmethyl magnesium chloride (22%) were slowly added, heating the mixtureat reflux for 3h. The reaction was quenched with TEA. Then a solution ofNaHCO₃ 7% was added and the aqueous phase was extracted with EtOAc. Thecrude product was purified on silica gel, affording compound 15 (75%)and the compound of di-methylation 16 (24%).

¹³C NMR (100 MHz, CDCl₃): δ 8.3; 14.6; 18.5; 21.1; 29.2; 30.4; 33.8;34.5; 35.5; 37.2; 43.2; 50.7; 51.8; 52.9; 62.3; 73.5; 100.1; 117.0;137.7; 156.1; 219.2.

Example 19 Synthesis of Compound 15 (Methylation)

200 mg of compound 3 were dissolved in 1.0 mL of THF and cooled at 0° C.Then 2.2 mL of Methyl Lithium (3%) were slowly added and stirred themixture for 3h at 0° C. The reaction was quenched with TEA. Then asolution of NaHCO₃ 7% was added, and the aqueous phase was extractedwith EtOAc. The crude product was purified on silica gel, affordingcompound 15 (76%) and the compound of di-methylation 16 (23%).

What is claimed is:
 1. A process for the preparation of a compound offormula (I), or a solvate thereof

wherein X represents H or it forms together with the carbon atom towhich it is bonded a ketone protecting group; Y together with the carbonatom to which it is bonded represents C═CH₂ or C(OH)CH₂Z, wherein Z isselected from H and SiR′₃ wherein each R′ is independently selected fromC₁-C₆ alkyl and C₆-C₁₀ aryl; R⁶ is selected from H, C₁-C₆ alkyl andhalogen; R¹⁰ is selected from H, C₁-C₆ alkyl and halogen, or is absentwhen there is a double bond between C₁ and C₁₀; R¹³ is selected from Hand C₁-C₆ alkyl; R¹⁶ is selected from H, C₁-C₆ alkyl and halogen; - - -is a single or double bond; which comprises reacting a compound offormula (II) or a solvate thereof

wherein X, R⁶, R¹⁰, R¹³, R¹⁶, and - - - have the meanings defined above;with a compound of formula (III)

wherein Z is selected from H and SiR′₃ wherein each R′ is independentlyselected from C₁-C₆ alkyl and C₆-C₁₀ aryl and M is selected from Li,MgBr, MgCl and Mgl.
 2. The process according to claim 1, wherein R⁶,R¹⁰, R¹⁶ are H; and R¹³ is selected from C₁-C₆ alkyl.
 3. The processaccording to claim 1, wherein Z represents a SiR′₃ group wherein each R′is independently selected from C₁-C₆ alkyl and C₆-C₁₀ aryl.
 4. Theprocess according to claim 1, wherein Y together with the carbon atom towhich it is bonded represents C═CH₂.
 5. The process according to claim4, which comprises: (a) reacting a compound of formula (II), or asolvate thereof, with a compound of formula (III) to obtain a compoundof formula (I), or a solvate thereof, wherein Y together with the carbonatom to which it is bonded represents a C(OH)CH₂Z group, wherein Z isselected from H and SiR′₃, wherein each R′ is independently selectedfrom C₁-C₆ alkyl and C₆-C₁₀ aryl; and (b) treating a compound of formula(I), or a solvate thereof, wherein Y together with the carbon atom towhich it is bonded represents a C(OH)CH₂Z group, wherein Z is selectedfrom H and SiR′₃, wherein each R′ is independently selected from C₁-C₆alkyl and C₆-C₁₀ aryl, with an acid or a base to obtain a compound offormula (I), or a solvate thereof, wherein Y together with the carbonatom to which it is bonded represents C═CH₂.
 6. The process according toclaim 1, which further comprises ethynylating the compound of formula(I), or a solvate thereof, to obtain a compound of formula (IV), or asolvate thereof

wherein Y, R⁶, R¹⁰, R¹³, R¹⁶ and - - - are as defined in claim 1; Xrepresents H or it forms together with the carbon atom to which it isbonded a ketone group or a ketone protecting group; and R¹ is selectedfrom H and SiR″₃, wherein each R″ is independently selected from C₁-C₆alkyl, C₆-C₁₀ aryl and halogen.
 7. The process according to claim 6,which comprises: (a) reacting a compound of formula (II), or a solvatethereof, with a compound of formula (III) to obtain a compound offormula (I), or a solvate thereof, wherein Y together with the carbonatom to which it is bonded represents a C(OH)CH₂Z group, wherein Z isselected from H and SiR′₃ wherein each R′ is independently selected fromC₁-C₆ alkyl and C₆-C₁₀ aryl; (b) treating a compound of formula (I), ora solvate thereof, wherein Y together with the carbon atom to which itis bonded represents a C(OH)CH₂Z group, wherein Z is selected from H andSiR′₃, wherein each R′ is independently selected from C₁-C₆ alkyl andC₆-C₁₀ aryl, with an acid or a base to obtain a compound of formula (I),or a solvate thereof, wherein Y together with the carbon atom to whichit is bonded represents C═CH₂; and (c) ethynylating a compound offormula (I), or a solvate thereof, wherein Y together with the carbonatom to which it is bonded represents C═CH₂, to obtain a compound offormula (IV), or a solvate thereof, wherein Y together with the carbonatom to which it is bonded represents C═CH₂.
 8. The process according toclaim 7, which comprises: (a) reacting a compound of formula (II), or asolvate thereof, with a compound of formula (III) to obtain a compoundof formula (I), or a solvate thereof, wherein Y together with the carbonatom to which it is bonded represents a C(OH)CH₂Z group, wherein Z isselected from H and SiR′₃, wherein each R′ is independently selectedfrom C₁-C₆ alkyl and C₆-C₁₀ aryl; (b) ethynylating a compound of formula(I), or a solvate thereof, wherein Y together with the carbon atom towhich it is bonded represents a C(OH)CH₂Z group, wherein Z is selectedfrom H and SiR′₃ wherein each R′ is independently selected from C₁-C₆alkyl and C₆-C₁₀ aryl, to obtain a compound of formula (IV), or asolvate thereof, wherein Y together with the carbon atom to which it isbonded represents a C(OH)CH₂Z group, wherein Z is selected from H andSiR′₃ wherein each R′ is independently selected from C₁-C₆ alkyl andC₆-C₁₀ aryl; and (c) treating a compound of formula (IV), or a solvatethereof, wherein Y together with the carbon atom to which it is bondedrepresents a C(OH)CH₂Z group, wherein Z is selected from H and SiR′₃,wherein each R′ is independently selected from C₁-C₆ alkyl and C₆-C₁₀aryl, with an acid or a base to obtain a compound of formula (IV), or asolvate thereof, wherein Y together with the carbon atom to which it isbonded represents C═CH₂.
 9. A process for the preparation ofDesogestrel, Etonogestrel, or a solvate thereof, the process comprising:preparing a compound of formula (I) or a solvate thereof

wherein X represents H or it forms together with the carbon atom towhich it is bonded a ketone protecting group; Y together with the carbonatom to which it is bonded represents C═CH₂ or C(OH)CH_(2Z), wherein Zis selected from H and SiR′₃ wherein each R′ is independently selectedfrom C₁-C₆ alkyl and C₆-C₁₀ aryl; R⁶ is selected from H, C₁-C₆ alkyl andhalogen; R¹⁰ is selected from H, C₁-C₆ alkyl and halogen, or is absentwhen there is a double bond between C₁ and C₁₀;R¹³ is selected from Hand C₁-C₆ alkyl; R¹⁶ is selected from H, C₁-C₆ alkyl and halogen; - - -is a single or double bond; by reacting a compound of formula (II) or asolvate thereof

wherein X, R⁶, R¹⁰, R¹³, R¹⁶, and - - - have the meanings defined above;with a compound of formula (III)

wherein Z is selected from H and SiR′₃ wherein each R′ is independentlyselected from C₁-C₆ alkyl and C₆-C₁₀ aryl and M is selected from Li,MgBr, MgCI and MgI; and converting the compound of formula (I), or asolvate thereof to Desogestrel, Etonogestrel, or a solvate thereof. 10.The process according to claim 9, wherein converting to Etonogestrel, ora solvate thereof, comprises the following steps: (a) reacting acompound of formula (IIa), or a solvate thereof,

wherein X forms together with the carbon atom to which it is bonded aketone protecting group; and - - - is a single or double bond; with acompound of formula (III)

wherein M is selected from Li, MgBr, MgCl and MgI; and Z is selectedfrom H and SiR′₃ wherein each R′ is independently selected from C₁-C₆alkyl and C₆-C₁₀ aryl; to afford a compound of formula (Ia-1) or asolvate thereof

(b) treating a compound of formula (Ia-1), or a solvate thereof, with anacid or a base to afford a compound of formula (Ia-2), or a solvatethereof,

(c) ethynylating a compound of formula (Ia-2), or a solvate thereof, toafford a compound of formula (IVa-1), or a solvate thereof

wherein X forms together with the carbon atom to which it is bonded aketone group or a ketone protecting group R¹ is selected from H andSiR″₃, wherein each R″ is independently selected from C₁-C₆ alkyl,C₆-C₁₀ aryl and halogen; and (d) if necessary, carrying out one or bothof the following steps in any order: (i) if X forms together with thecarbon atom to which it is bonded a ketone protecting group, cleavage ofthe ketone protecting group to afford a compound of formula (IVa-1), ora solvate thereof, wherein X forms together with the carbon atom towhich it is bonded a ketone group, (ii) if R¹ is a SiR″₃ group, removalof the SiR″₃ group to afford a compound of formula (IVa-1), or a solvatethereof, wherein R¹ is H.
 11. The process according to claim 9, whereinconverting to Etonogestrel, or a solvate thereof, comprises thefollowing steps: (a) reacting a compound of formula (IIa), or a solvatethereof,

wherein X forms together with the carbon atom to which it is bonded aketone protecting group; and - - - is a single or double bond; with acompound of formula (III)

wherein M is selected from Li, MgBr, MgCl and MgI; and Z is selectedfrom H and SiR′₃ wherein each R′ is independently selected from C₁-C₆alkyl and C₆-C₁₀ aryl; to afford a compound of formula (Ia-1), or asolvate thereof,

(b) ethynylating a compound of formula (Ia-1), or a solvate thereof, toafford a compound of formula (IVa-2), or a solvate thereof

wherein R¹ is selected from H and SiR″₃, wherein each R″ isindependently selected from C₁-C₆ alkyl, C₆-C₁₀ aryl and halogen; (c)treating a compound of formula (IVa-2), or a solvate thereof, with anacid or a base to afford a compound of formula (IVa-1), or a solvatethereof

wherein X forms together with the carbon atom to which it is bonded aketone group or a ketone protecting group R¹ is selected from H andSiR″₃, wherein each R″ is independently selected from C₁-C₆ alkyl,C₆-C₁₀ aryl and halogen; and (d) if necessary, carrying out one or bothof the following steps in any order: (i) if X forms together with thecarbon atom to which it is bonded a ketone protecting group, cleavage ofthe ketone protecting group to afford a compound of formula (IVa-1), ora solvate thereof, wherein X forms together with the carbon atom towhich it is bonded a ketone group, (ii) if R¹ is a SiR″₃ group, removalof the SiR″₃ group to afford a compound of formula (IVa-1), or a solvatethereof, wherein R¹ is H.
 12. The process according to claim 9, whereinconverting to Desogestrel, or a solvate thereof, comprises the followingsteps: (a) reacting compound (12), or a solvate thereof,

with a compound of formula (III)

wherein M is selected from Li, MgBr, MgCl and MgI; and Z is selectedfrom H and SiR′₃ wherein each R′ is independently selected from C₁-C₆alkyl and C₆-C₁₀ aryl; to afford a compound of formula (Ib-1) or asolvate thereof

(b) treating a compound of formula (Ib-1), or a solvate thereof, with anacid or a base to afford a compound of formula (Ib-2), or a solvatethereof,

(c) ethynylating a compound of formula (Ib-2), or a solvate thereof, toafford a compound of formula (IVb-1), or a solvate thereof

wherein R¹ is selected from H and SiR″₃, wherein each R″ isindependently selected from C₁-C₆ alkyl, C₆-C₁₀ aryl and halogen; and(d) if R¹ is a SiR″₃ group, removing SiR″₃ group to afford Desogestrel,or a solvate thereof.